1. Field of the Invention
The present invention relates generally to the fields diabetes. More particularly, it concerns the identification of genes responsible for diabetes for use in diagnostics and therapeutics.
2. Description of Related Art
Diabetes is a major cause of health difficulties in the United States. Non-insulin-dependent diabetes mellitus (NIDDM also referred to as Type 2 diabetes) is a major public health disorder of glucose homeostasis affecting about 5% of the general population in the United States. The causes of the fasting hyperglycemia and/or glucose intolerance associated with this form of diabetes are not well understood.
Clinically, NIDDM is a heterogeneous disorder characterized by chronic hyperglycemia leading to progressive micro- and macrovascular lesions in the cardiovascular, renal and visual systems as well as diabetic neuropathy. For these reasons, the disease may be associated with early morbidity and mortality.
Subtypes of the NIDDM can be identified based at least to some degree on the time of onset of the symptoms. The principal type of NIDDM has on-set in mid-life or later. Early-onset NIDDM or maturity-onset diabetes of the young (MODY) shares many features with the more common form(s) of NIDDM whose onset occurs in mid-life. Maturity-onset diabetes of the young (MODY) is a form of non-insulin dependent (Type 2) diabetes mellitus (NIDDM) that is characterized by an early age at onset, usually before 25 years of age, and an autosomal dominant mode of inheritance (Fajans 1989). Except for these features, the clinical characteristics of patients with MODY are similar to those with the more common late-onset form(s) of NIDDM.
Although most forms of NIDDM do not exhibit simple Mendelian inheritance, the contribution of heredity to the development of NIDDM has been recognized for many years (Cammidge 1928) and the high degree of concordance of NIDDM in monozygotic twin pairs (Barnett et al. 1981) indicates that genetic factors play an important role in its development.
MODY is characterized by its early age of onset which is during childhood, adolescence or young adulthood and usually before the age of 25 years. It has a clear mode of inheritance being autosomal dominant. Further characteristics include high penetrance (of the symptomology), and availability of multigenerational pedigrees for genetic studies of NIDDM. MODY occurs worldwide and has been found to be a phenotypically and genetically heterogeneous disorder.
A number of genetically distinct forms of MODY have been identified. Genetic studies have shown tight linkage between MODY and DNA markers on chromosome 20, this being the location of the MODY1 gene (Bell et al., 1991; Cox et al., 1992). MODY2 is associated with mutations in the glucokinase gene (GCK) located on chromosome 7 (Froguel et al. 1992 and 1993). Recent linkage studies have shown the existence of a further form of MODY which has been termed MODY3 (Vaxillaire et al., 1995). MODY3 has been shown to be linked to chromosome 12 and is localized to a 5 cM region between markers D12S86 and D12S807/D12S820 of the chromosome (Menzel et al., 1995).
Although it is well established that MODY2 is associated with mutations in GCK there is still no information as to the identity of other MODY genes. There is a clear need to identify these genes and the mutations that result in diseased states. The identification of these genes and their products will facilitate a better understanding of the diseased states associated with mutations in these genes and has important implications in the diagnosis and therapy of MODY.
Since an understanding of the molecular basis of diabetes in general and MODY specifically may facilitate the development of new therapeutic strategies for the treatment of these disorders, studies are needed to identify diabetes-susceptibility genes associated with MODY. Moreover, methods of detecting individuals with a propensity to develop such diseases are needed. Where possible, the molecular mechanism underpinning the genetic lesion should be determined in order to allow diagnosis and specifically-directed therapy.